ArticleBioorganic & medicinal chemistry letters2015
The combination of thioxodihydroquinazolinones and platinum drugs reverses platinum resistance in tumor cells by inducing mitochondrial apoptosis independent of Bax and Bak.
Article in Bioorganic & medicinal chemistry letters, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 15 citations in OpenAlex.
- Cell-active small molecule inhibitors validate the SNM1A DNA repair nuclease as a cancer target.Chemical science · 2024Article
- Mitochondrial Dynamin-Related Protein Drp1: a New Player in Cardio-oncology.Current oncology reports · 2022Review
- Oxidative stress-mediated mitochondrial fission promotes hepatic stellate cell activation via stimulating oxidative phosphorylation.Cell death & disease · 2022Article
- Combination of a thioxodihydroquinazolinone with cisplatin eliminates ovarian cancer stem cell-like cells (CSC-LCs) and shows preclinical potential.Oncotarget · 2018Article
- Dark and Photoinduced Cytotoxic Activity of the New Chlorophyll-a Derivatives with Oligoethylene Glycol Substituents on the Periphery of Their Macrocycles.International journal of molecular sciences · 2017Article
- Inhibition of Mitochondrial Division Attenuates Cisplatin-Induced Toxicity in the Neuromast Hair Cells.Frontiers in cellular neuroscience · 2017Article
- Mitochondrial fission - a drug target for cytoprotection or cytodestruction?Pharmacology research & perspectives · 2016Review
- Apoptosis of human pancreatic carcinoma cell-1 cells induced by Yin Chen Hao Decoction.World journal of gastroenterology · 2015Article
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
The effective management of tumors resistant to platinum drugs-based anticancer therapies is a critical challenge in current clinical practices. The proapoptotic Bcl-2 family proteins Bax and Bak are essential for cisplatin-induced apoptosis. Unfortunately, Bax and its related upstream endogenous apoptotic signaling pathways are often dysregulated in cancer cells. Strategies that are able to bypass Bax- and Bak-dependent apoptotic pathways will thus provide opportunities to overcome platinum drug resistance. We have identified the thioxodihydroquinazolinone mdivi-1 as a member of a novel class of small molecules that are able to induce Bax- and Bak-independent mitochondrial outer membrane permeabilization when combined with cisplatin, thereby efficiently triggering apoptosis in platinum-resistant tumor cells. In the present structure activity relationship (SAR) study of a computationally selected library of mdivi-1 related small molecules, we established a pharmacophore model that can lead to the enhancement of platinum drug efficacy and Bax/Bak-independent mitochondrial apoptosis. Specifically, we found that a thiourea function is necessary but not sufficient for the synergism of this class of thioxodihydroquinazolinones with cisplatin. We were also able to identify more potent mdivi-1 analogs through this SAR study, which will guide future designs with the goal to develop novel combination regimens for the treatment of platinum- and multidrug-resistant tumors.
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